Cannabinoids and the expanded endocannabinoid system in neurological disorders.

 Related image“Anecdotal evidence that cannabis preparations have medical benefits together with the discovery of the psychotropic plant cannabinoid Δ9-tetrahydrocannabinol (THC) initiated efforts to develop cannabinoid-based therapeutics.

These efforts have been marked by disappointment, especially in relation to the unwanted central effects that result from activation of cannabinoid receptor 1 (CB1), which have limited the therapeutic use of drugs that activate or inactivate this receptor.

The discovery of CB2 and of endogenous cannabinoid receptor ligands (endocannabinoids) raised new possibilities for safe targeting of this endocannabinoid system. However, clinical success has been limited, complicated by the discovery of an expanded endocannabinoid system – known as the endocannabinoidome – that includes several mediators that are biochemically related to the endocannabinoids, and their receptors and metabolic enzymes.

The approvals of nabiximols, a mixture of THC and the non-psychotropic cannabinoid cannabidiol, for the treatment of spasticity and neuropathic pain in multiple sclerosis, and of purified botanical cannabidiol for the treatment of otherwise untreatable forms of paediatric epilepsy, have brought the therapeutic use of cannabinoids and endocannabinoids in neurological diseases into the limelight.

In this Review, we provide an overview of the endocannabinoid system and the endocannabinoidome before discussing their involvement in and clinical relevance to a variety of neurological disorders, including Parkinson disease, Alzheimer disease, Huntington disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, stroke, epilepsy and glioblastoma.”

https://www.ncbi.nlm.nih.gov/pubmed/31831863

“The existence of the endocannabinoidome explains in part why some non-euphoric cannabinoids, which affect several endocannabinoidome proteins, are useful for the treatment of neurological disorders, such as multiple sclerosis and epilepsy.”

https://www.nature.com/articles/s41582-019-0284-z

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Bone Anabolic Response in the Calvaria Following Mild Traumatic Brain Injury is Mediated by the Cannabinoid-1 Receptor.

 Scientific Reports“Brain trauma was clinically associated with increased osteogenesis in the appendicular skeleton. We showed previously in C57BL/6J mice that mild traumatic brain injury (mTBI) transiently induced bone formation in the femur via the cannabinoid-1 (CB1) receptor. Here, we subjected ICR mice to mTBI and examined the bone response in the skull using microCT. We also measured mast cell degranulation (MCD)72 h post-injury. Finally, we measured brain and calvarial endocannabinoids levels post-mTBI. mTBI led to decreased bone porosity on the contralateral (untouched) side. This effect was apparent both in young and mature mice. Administration of rimonabant (CB1 inverse agonist) completely abrogated the effect of mTBI on calvarial porosity and significantly reduced MCD, compared with vehicle-treated controls. We also found that mTBI resulted in elevated levels of anandamide, but not 2-arachidonoylglycerol, in the contralateral calvarial bone, whereas brain levels remained unchanged. In C57BL/6J CB1 knockout mice, mTBI did not reduce porosity but in general the porosity was significantly lower than in WT controls. Our findings suggest that mTBI induces a strain-specific CB1-dependent bone anabolic response in the skull, probably mediated by anandamide, but seemingly unrelated to inflammation. The endocannabinoid system is therefore a plausible target in management of bone response following head trauma.”

https://www.ncbi.nlm.nih.gov/pubmed/31700010

https://www.nature.com/articles/s41598-019-51720-w

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Cannabis, alcohol and cigarette use during the acute post-concussion period.

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“Objective: To document the prevalence of acute post-concussion cannabis, alcohol and cigarette use and their association with clinical recovery and symptom burden.

Results: A total of 307 acute concussions with a mean age of 33.7 years (SD, 13.0) were included. Acute post-concussion cannabis, alcohol and cigarette use were identified in 43 (14.0%), 125 (40.7%) and 61 (19.9%) individuals. Acute cannabis, alcohol and cigarette use were not associated with recovery to cognitive (p > .05) or physical activity (p > .05). Acute cigarette use was associated with a higher unadjusted symptom severity score at week1 (p = .003). Acute cannabis use was associated with lower symptom severity scores at week-3 (p = .061) and week-4 (p = .029).

Conclusion: In conclusion, cannabis, alcohol and cigarette use were prevalent in the acute period post-concussion; however, were not observed to impact recovery within the first 4 weeks post-injury. Amongst unrecovered individuals, acute cannabis use was associated with lower symptom burden, while cigarette use was associated with greater initial symptom burden.”

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Cannabidiol improves vocal learning-dependent recovery from, and reduces magnitude of deficits following, damage to a cortical-like brain region in a songbird pre-clinical animal model.

Neuropharmacology“Cannabidiol (CBD), a non-euphorigenic compound derived from Cannabis, shows promise for improving recovery following cerebral ischemia and has recently been shown effective for the treatment of childhood seizures caused by Dravet and Lennox-Gastaut syndromes.

Given evidence for activity to mitigate effects of CNS insult and dysfunction, we considered the possibility that CBD may also protect and improve functional recovery of a complex learned behavior. To test this hypothesis, we have applied a songbird, the adult male zebra finch, as a novel pre-clinical animal model.

Results indicate 10 and 100 mg/kg CBD effectively reduced the time required to recover vocal phonology and syntax. In the case of phonology, the magnitude of microlesion-related disruptions were also reduced.

These results suggest CBD holds promise to improve functional recovery of complex learned behaviors following brain injury, and represent establishment of an important new animal model to screen drugs for efficacy to improve vocal recovery.”

https://www.ncbi.nlm.nih.gov/pubmed/31325430

https://www.sciencedirect.com/science/article/pii/S0028390818305343?via%3Dihub

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The Endocannabinoid System and its Modulation by Cannabidiol (CBD).

Image result for Altern Ther Health Med. “The endocannabinoid system (ECS) is an extensive endogenous signaling system with multiple elements, the number of which may be increasing as scientists continue to elucidate its role in human health and disease. The ECS is seemingly ubiquitous in animal species and is modulated by diet, sleep, exercise, stress, and a multitude of other factors, including exposure to phytocannabinoids, like Cannabidiol (CBD). Modulating the activity of this system may offer tremendous therapeutic promise for a diverse scope of diseases, ranging from mental health disorders, neurological and movement disorders, pain, autoimmune disease, spinal cord injury, cancer, cardiometabolic disease, stroke, TBI, osteoporosis, and others.”

https://www.ncbi.nlm.nih.gov/pubmed/31202198

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Effects of cannabidiol on alcohol-related outcomes: A review of preclinical and human research.

Cover image for Experimental and Clinical Psychopharmacology

“This article reviews preclinical and human studies examining the effects of CBD administration on alcohol responses. Preliminary preclinical results suggest that CBD can attenuate alcohol consumption and potentially protect against certain harmful effects of alcohol, such as liver and brain damage.”

https://www.ncbi.nlm.nih.gov/pubmed/31120285

https://psycnet.apa.org/doiLanding?doi=10.1037%2Fpha0000272

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Therapeutic prospects of cannabidiol for alcohol use disorder and alcohol-related damages on the liver and the brain

 Image result for frontiers in pharmacology“Cannabidiol (CBD) is a natural compound of cannabis, which exerts complex and widespread immunomodulatory, antioxidant, anxiolytic, and antiepileptic properties. Many experimental data suggest that CBD could have several types of application in alcohol use disorder (AUD) and alcohol-related damage on the brain and the liver.

Experimental studies converge to find that CBD reduces the overall level of alcohol drinking in animal models of AUD by reducing ethanol intake, motivation for ethanol, relapse, and by decreasing anxiety and impulsivity. Moreover, CBD has been shown to reduce alcohol-related steatosis and fibrosis in the liver by reducing lipid accumulation, stimulating autophagy, modulating inflammation, reducing oxidative stress, and inducing death of activated hepatic stellate cells. Last, CBD has been found to reduce alcohol-related brain damage, preventing neuronal loss by its antioxidant and immunomodulatory properties.

CBD could directly reduce alcohol drinking in subjects with AUD. But other original applications warrant human trials in this population. By reducing alcohol-related processes of steatosis in the liver, and brain alcohol-related damage, CBD could improve both the hepatic and neurocognitive outcomes of subjects with AUD, regardless of the individual drinking trajectories. This might pave the way for testing new harm reduction approaches in AUD, i.e., for protecting the organs of subjects with an ongoing AUD.”

https://www.frontiersin.org/articles/10.3389/fphar.2019.00627/abstract

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Oral Cannabidiol Prevents Allodynia and Neurological Dysfunctions in a Mouse Model of Mild Traumatic Brain Injury.

 Image result for frontiers in pharmacology“Neurological dysfunctions are the most impactful and persistent consequences of traumatic brain injury (TBI). Indeed, previous reports suggest that an association between TBI and chronic pain syndromes, as well anxio-depressive behaviors, tends to be more common in patients with mild forms of TBI. At present, no effective treatment options are available for these symptoms.

In the present study, we used a weight drop mild TBI mouse model to investigate the effect of a commercially available 10% Cannabidiol (CBD) oil on both the sensorial and neuropsychiatric dysfunctions associated with mild TBI through behavioral and biomolecular approaches.

TBI mice developed chronic pain associated with anxious and aggressive behavior, followed by a late depressive-like behavior and impaired social interaction. Such behaviors were related with specific changes in neurotransmitters release at cortical levels.

CBD oral treatment restored the behavioral alterations and partially normalized the cortical biochemical changes.

In conclusion, our data show some of the brain modifications probably responsible for the behavioral phenotype associated with TBI and suggest the CBD as a pharmacological tool to improve neurological dysfunctions caused by the trauma.”

https://www.ncbi.nlm.nih.gov/pubmed/31040777

https://www.frontiersin.org/articles/10.3389/fphar.2019.00352/full

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Pre- and post-conditioning treatment with an ultra-low dose of Δ9-tetrahydrocannabinol (THC) protects against pentylenetetrazole (PTZ)-induced cognitive damage.

Behavioural Brain Research

“Preconditioning, a phenomenon where a minor noxious stimulus protects from a subsequent more severe insult, and post-conditioning, where the protective intervention is applied following the insult, offer new insight into the neuronal mechanism(s) of neuroprotection and may provide new strategies for the prevention and treatment of brain damage. We have previously reported that a single administration of an extremely low dose of Δ(9)-tetrahydrocannabinol (THC; the psychoactive ingredient of marijuana) to mice induced minor long-lasting cognitive deficits.

In the present study we examined the possibility that such a low dose of THC will protect the mice from more severe cognitive deficits induced by the epileptogenic drug pentylenetetrazole (PTZ). THC (0.002 mg/kg, a dose that is 3-4 orders of magnitude lower than the doses that induce the conventional effects of THC) was administered 1-7 days before, or 1-3 days after the injection of PTZ (60 mg/kg). The consequences of this treatment were studied 3-7 weeks later by various behavioral tests that evaluated different aspects of memory and learning.

We found that a single administration of THC either before or after PTZ abolished the PTZ-induced long-lasting cognitive deficits.

Biochemical studies indicated a concomitant reduction in phosphorylated-ERK (extracellular signal-regulated kinase) in the cerebella of mice 7 weeks following the injection of THC.

Our results suggest that a pre- or post-conditioning treatment with extremely low doses of THC, several days before or after brain injury, may provide safe and effective long-term neuroprotection.”

https://www.ncbi.nlm.nih.gov/pubmed/21315768

https://www.sciencedirect.com/science/article/pii/S0166432811001094?via%3Dihub

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Increased expression of cannabinoid CB2 and serotonin 5-HT1A heteroreceptor complexes in a model of newborn hypoxic-ischemic brain damage.

Neuropharmacology

“Preclinical work shows cannabidiol as a promising drug to manage neonatal hypoxic-ischemic brain damage (NHIBD). The molecular mechanism is not well defined but the beneficial effects of this phytocannabinoid are blocked by antagonists of both cannabinoid CB2(CB2R) and serotonin 5-HT1A (5-HT1AR) receptors that, in addition, may form heteromers in a heterologous expression system. Using bioluminescence energy transfer, we have shown a direct interaction of the two receptors that leads to a particular signaling in a heterologous system. A property attributed to the heteromer, namely cross-antagonism, was found in primary cultures of neurons thus indicating the occurrence of the receptor heteromer in the CNS. Oxygen-glucose deprivation to neurons led to an increase of CB2R-mediated signaling and an upregulation of CB2-5-HT1A heteroreceptor complex expression. In situ proximity ligation assays in brain cortical section were performed to compare the expression of CB2-5-HT1A complexes in rat E20 fetuses and at different postnatal days. The expression, which is elevated in fetus and shortly after birth, was sharply reduced at later ages (even at P7). The expression of heteromer receptors was more marked in a model of NHIBD and, remarkably, the drop in expression was significantly delayed with respect to controls. These results indicate that CB2-5-HT1A heteroreceptor complex may be considered as a target in the therapy of the NHIBD.”

https://www.ncbi.nlm.nih.gov/pubmed/30738036

https://www.sciencedirect.com/science/article/pii/S0028390819300462?via%3Dihub

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